Acute Kidney Injury in Severe Sepsis and
Septic Shock in Patients with and without
Diabetes Mellitus: A Multicenter Study
Marion Venot1*, Lise Weis2, Christophe Clec’h3,4, Michael Darmon5,6, Bernard Allaouchiche7, Dany Goldgran-Tolédano8, Maité Garrouste-Orgeas9, Christophe Adrie10, Jean-François Timsit11,12, Elie Azoulay1,13
1Service de Réanimation Médicale, AP-HP, Hôpital Saint-Louis, Paris, France,2Service de Médecine Vasculaire et Hypertension artérielle, AP-HP, Hôpital Européen Georges Pompidou, Paris, France,
3Service de Réanimation, AP-HP, Hôpital Avicenne, Paris, France,4Faculté de Médecine, Université Paris 13, Bobigny, France,5Service de Réanimation Médicale, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France,6Faculté de Médecine Jacques Lisfranc, Université Jean Monnet, Saint-Etienne, France,7Service de Réanimation Chirurgicale, Centre Hospitalier Universitaire Edouard Herriot, Lyon, France,8Service de Réanimation Polyvalente, Centre Hospitalier de Gonesse, Gonesse, France,9Service de Réanimation Polyvalente, Groupe Hospitalier Paris Saint-Joseph, Paris, France,10Service de
Physiologie, AP-HP, Hôpital Cochin, Paris, France,11Service de Réanimation Polyvalente, Centre Hospitalier Universitaire de Grenoble, Grenoble, France,12U 823, Université de Grenoble 1, Grenoble, France,13Faculté de Médecine, Université Paris 5, Paris, France
*marion.venot@aphp.fr
Abstract
Introduction
Whether diabetes mellitus increases the risk of acute kidney injury (AKI) during sepsis is controversial.
Materials and Methods
We used a case-control design to compare the frequency of AKI, use of renal replacement therapy (RRT), and renal recovery in patients who had severe sepsis or septic shock with or without diabetes. The data were from the Outcomerea prospective multicenter database, in which 12 French ICUs enrolled patients admitted between January 1997 and June 2009.
Results
First, we compared 451 patients with severe sepsis or septic shock and diabetes to 3,277 controls with severe sepsis or septic shock and without diabetes. Then, we compared 318 cases (with diabetes) to 746 matched controls (without diabetes). Diabetic patients did not have a higher frequency of AKI (hazard ratio [HR], 1.18;P= 0.05]) or RRT (HR, 1.09;P= 0.6). However, at discharge, diabetic patients with severe sepsis or septic shock who expe-rienced acute kidney injury during the ICU stay and were discharged alive more often re-quired RRT (9.5% vs. 4.8%;P= 0.02), had higher serum creatinine values (134 vs. 103
µmoL/L;P<0.001) and had less often recovered a creatinine level less than 1.25 fold the basal creatinine (41.1% vs. 60.5%;P<0.001).
OPEN ACCESS
Citation:Venot M, Weis L, Clec’h C, Darmon M, Allaouchiche B, Goldgran-Tolédano D, et al. (2015) Acute Kidney Injury in Severe Sepsis and Septic Shock in Patients with and without Diabetes Mellitus: A Multicenter Study. PLoS ONE 10(5): e0127411. doi:10.1371/journal.pone.0127411
Academic Editor:Zaccaria Ricci, Bambino Gesù Children's Hospital, ITALY
Received:February 10, 2015
Accepted:April 14, 2015
Published:May 28, 2015
Copyright:© 2015 Venot et al. This is an open access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement:All relevant data are within the paper.
Conclusions
In patients with severe sepsis or septic shock, diabetes is not associated with occurrence of AKI or need for RRT but is an independent risk factor for persistent renal dysfunction in pa-tients who experience AKI during their ICU stay.
Introduction
Diabetes mellitus affects 10% of the general population [1] and is associated with high morbidi-ty and mortalimorbidi-ty rates. Sepsis and renal dysfunction are among the main complications of dia-betes [2;3]. Chronic kidney disease (CKD) is the most common renal dysfunction pattern in diabetes and may progress to kidney failure [4]. In industrialized countries, diabetes-related CKD is the leading cause of end-stage kidney failure [4].
The risk of acute kidney injury (AKI) during life-threatening events such as sepsis is in-creased in patients with diabetes, even those with the milder stages of CKD manifesting as small decreases in the glomerular filtration rate (GFR) [5]. Diabetes has been identified as an independent risk factor for AKI [6,7]. Moreover, acute-on-chronic kidney injury is associated with a need for long-term dialysis, failure to recover initial renal function, and death [8]. Sepsis is a major cause of AKI, which develops in one-fourth of all patients with sepsis and half of pa-tients with bacteremia or shock [9]. Sepsis-related AKI is associated with high mortality rates of up to 70% [9,10,11,12]. Whether diabetes increases the risk of AKI during sepsis is contro-versial [13,14]. However, diabetes is an established risk factor for both AKI and sepsis [2,3,4].
Here, our objective was to evaluate the impact of diabetes on kidney function in patients with severe sepsis or septic shock. We used a case-control design to compare the incidence of AKI, use of renal replacement therapy (RRT), and renal recovery in diabetic and nondiabetic patients with severe sepsis or septic shock enrolled in a prospective database by 12 intensive care units (ICUs).
Materials and Methods
Study design and data source
Outcomerea is a prospective observational multicenter database established between January 1997 and June 2009 by 12 French ICUs. To avoid selection bias and ensure external validity, a random sample of patients older than 16 years of age and admitted for>24 hours were entered into the database each year. Participating centers could enroll either consecutive patients mitted to a prespecified number of beds throughout each year or all consecutive patients ad-mitted during a prespecified month. The number of beds or month of enrolment were decided yearly by the database steering committee. Detailed clinical and outcome data were recorded prospectively for each patient, on a daily basis, by senior ICU physicians with assistance from trained study monitors in each participating ICU. Data were recorded at baseline (including demographic characteristics, comorbidities, baseline severity, admission diagnosis, admission category, and patient location just before ICU admission) then on each ICU day (including di-agnostic and therapeutic procedures, laboratory parameters, organ failures, sepsis, iatrogenic events, and treatment-limitation decisions). For each patient, the data were entered into an electronic case-report form using VIGIREA and RHEA data-capture software (Outcomerea, Rosny-sous-Bois, France) and all case-report forms were then entered into the Outcomerea data warehouse. The data-capture software automatically conducted multiple checks for companies and none of their relationship with
industrial companies are related to the topic covered by this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
internal consistency of most of the variables at entry into the database. Queries generated by these checks were resolved with the source ICU before incorporation of the new data into the database. At each participating ICU, data quality was controlled by having a senior physician from another participating ICU check a 2% random sample of the study data. A 1-day coding course was held annually with the study investigators and study monitors.
In accordance with French law, approval for the development and maintenance of the Out-comerea database was obtained from the data confidentiality agency Commission Nationale de l’Informatique et des Libertés. The study was approved by the ethics committee in Clermont-Ferrand, France. Given the observational study design, absence of effect of data collection on patient management, and use of anonymized data for the statistical analyses, the ethics com-mittee waived the requirement for informed consent from study patients. The senior physi-cians and centers that participated in Outcomerea are listed in the acknowledgment section.
Study population
Cases were consecutive patients with severe sepsis or septic shock and diabetes. Controls were consecutive patients with severe sepsis or septic shock and no diabetes. Diabetic status was as-sessed based on previous medical history as reported by patients, relatives or consultants. We excluded patients with CKD (MDRD eGFR less than 60ml/min, when baseline creatinine was available), prerenal AKI (rapidly reversible AKI less than 48 hours), extrarenal indications for dialysis (tumor lysis syndrome, Metformine related lactic acidosis), or treatment-limitation de-cisions. We compared all cases to all controls then a subset of cases to matched controls.
Matching procedure
Using an algorithm (available at:http://www.outcomerea.org/Macros-SAS/Voir-categorie. html), diabetic patients (exposed population) were matched to nondiabetic patients (unex-posed population) on the following risk factors for CKD and AKI: age (±5 years), SAPS II score (±5 points), and underlying cardiac comorbidity (New York Heart Association (NYHA) class IV heart failure) assessed according to Acute Physiology and Chronic Health Evaluation (APACHE) II definitions. Additional matching criteria were center and period of admission (1997–2002 and 2003–2009) to account for variations in RRT practices over time and across centers. Up to 3 controls could be selected for each case.
Endpoints and analysis
Comparisons between cases and controls focused on three points: occurrence of AKI defined as any KDIGO category (using the only serum creatinine criteria), need for RRT, and renal function at discharge as assessed by the KDIGO category, creatinine level, weaning from RRT, and renal recovery defined as a creatinine level less than 1.25 fold the basal creatinine.
Statistical analysis
determine the significance of each variable. Adjusted odds ratios (ORs) and 95% confidence in-tervals (CIs) were calculated for each parameter estimate.
Pvalues less than 0.05 were considered significant. Analyses were performed using the SAS 9.1 software package (SAS Institute, Cary, NC, USA).
Results
As shown inFig 1, among the 10 911 patients admitted to the 12 participating ICUs over the 13-year study period (1997–2010), 3728 had severe sepsis (n = 3218) or septic shock (n = 510). Among them, 451 had diabetes and 3277 did not. For the matched analysis, 318 (71%) cases had 746 matched controls.
Patient characteristics
Table 1reports the baseline characteristics of the cases and controls. The acute illness was more severe and cardiac comorbidities more common in the group with diabetes. Mortality was higher in the diabetic patients but the difference was not statistically significant (19.8% vs. 15% in the matched case-control analysis;P= 0.08).
Occurrence of acute kidney injury (AKI) and use of renal replacement
therapy (RRT)
Both AKI and use of RRT were significantly more common in the patients with diabetes in the analysis comparing all cases to all controls (Table 2).
However, no difference in the frequency of AKI was found in the matched case-control analysis (Table 3), even after adjustment for nephrotoxic drugs, duration of hemodynamic fail-ure, and chronic comorbidities. When we confined the matched analysis to cases with insulin-dependent diabetes and their controls, we found a significantly higher frequency of AKI in the diabetic patients, but this difference was no longer apparent after adjustment for nephrotoxic drugs, duration of hemodynamic failure, and underlying condition. Similarly, the use of RRT was not more common in the cases in the matched case-control analysis (Table 3), even after adjustment for nephrotoxic drugs, duration of hemodynamic failure, and chronic comorbidi-ties. Confining this analysis to cases with insulin-dependent diabetes and their controls did not show a difference in the use of RRT.
Renal function at discharge (
Table 4
)
In the overall cohort, 244 (74.6%) of 327 patients with diabetes and AKI were discharged alive compared to 1312 (71.6%) of 1832 patients with AKI and without diabetes. Neither use of RRT nor renal function recovery were significantly different between all cases and all controls. Serum creatinine at discharge in patients who did not need RRT was significantly higher in dia-betic than nondiadia-betic patients. Proportions of patients with KDIGO category 3 at discharge were not different between the two groups.
Discussion
Diabetes mellitus is a highly prevalent condition [1] associated with both AKI and sepsis [2,3,
4]. Few studies assessed the impact of having diabetes on the risk of AKI during sepsis, which is a current focus of controversy [13,14]. We conducted a multicenter study of prospectively col-lected data using a matched case-control design to determine whether diabetes increased the risk and worsened the prognosis of AKI during severe sepsis or septic shock. Our results Fig 1. Patient flow chart.
showed that having diabetes did not increase the risk of AKI or RRT but worsened the renal prognosis at discharge, as assessed based on need for RRT, serum creatinine level, and recovery of previous renal function.
Among patients admitted to the ICU, 35% to 70% develop AKI, which is related to sepsis in half the cases. AKI has been reported in 19% of patients with sepsis, 23% of those with severe sepsis, and 51% of those with septic shock and bacteremia [4,9]. In a prospective multicenter study, 70% of patients with AKI and sepsis died, compared to 45% of those with AKI and no sepsis [10]. The development of AKI during sepsis has been reported to increase mortality (OR, 1.53) and hospital stay length [11,12]. Given this major impact of AKI during sepsis, de-termining the effect of diabetes on the risk and prognosis of AKI is of considerable interest. Di-abetes is an established independent risk factor for AKI [6,7], both overall and during sepsis [14], and the risk of sepsis of any type is 2.5-fold to 6-fold higher in patients with diabetes than in the general population [3,15,16,17,18,19]. Diabetes increased the risk of death from infec-tious causes in one study [20] but did not affect mortality in a study focusing on severe sepsis [21]. Pre-existing kidney diseases such as diabetes-related CKD may increase the risk of devel-oping AKI during sepsis [22] [23], and, diabetes itself may also increase the risk of AKI during Table 1. Baseline characteristics of patients with severe sepsis or septic shock with (cases) or without (controls) diabetes mellitus.
All cases and controls Matched cases and controls
Diabetes (N = 451) No diabetes (N = 3277) Pvalue Diabetes (N = 318) No diabetes (N = 746) Pvalue
Age, mean (SD) 67.3 (12.2) 61.7 (16.5) <0.001 67.6 (11.7) 67.3 (12.5) 0.7 Males, n (%) 249 (61.9) 2062 (62.9) 0.7 197 (62.8) 490 (65.7) 0.2 SAPS II score, mean (SD) 53.7 (21.2) 48.1 (19.7) <0.001 50.6 (17.10) 48.6 (16) 0.06 APACHE II score, mean (SD) 20.6 (7.3) 18.7 (7.2) <0.001 20.1 (6.8) 18.9 (6.5) 0.02 Transfer from ward, n (%) 223 (49.5) 1649 (50.3) 0.7 156 (49.1) 401 (53.8) 0.2
McCabe, n (%) 0.5 0.1
1 261 (58) 1852 (56.5) 173 (54.4) 445 (59.6)
2 149 (33) 1206 (36.8) 126 (39.6) 266 (35.7)
3 41 (9) 219 (6.7) 19 (6) 35 (4.7)
Admission category, n (%) 0.007 0.1
Medical 341 (75.6) 2238 (68.3) 233 (73.3) 492 (66.1)
Scheduled surgery 68 (15.1) 629 (19.2) 54 (17) 160 (21.4) Unscheduled surgery 42 (9.3) 410 (12.5) 31 (9.7) 94 (12.5) Chronic comorbidities, n (%)
Heart disease 91 (20.2) 392 (12) <0.001 65 (20.4) 75 (10) <0.001 Respiratory disease 69 (15.3) 457 (14) 0.4 45 (14.1) 116 (15.6) 0.7
Liver disease 45 (10) 238 (7.3) 0.04 34 (10.7) 52 (7) 0.07
Immunodeficiency 53 (11.8) 571 (17.4) 0.002 40 (12.6) 112 (15) 0.3 ICU mortality, n (%) 99 (22) 674 (20.6) 0.5 63 (19.8) 112 (15) 0.08 ICU stay length, days (SD) 11.6 (12.8) 13.2 (15.2) 0.02 9.1 (8.5) 16.8 (17.5) 0.01
doi:10.1371/journal.pone.0127411.t001
Table 2. Acute kidney injury and renal replacement therapy in patients with severe sepsis or septic shock: comparison of all cases (with diabetes) and controls (without diabetes).
Diabetes (N = 451) No diabetes (N = 3277) Pvalue
Acute kidney injury, n (%) 327 (72.5) 1832 (55.9) <0.001
Renal replacement therapy, n (%) 93 (20.6) 452 (13.8) <0.01
sepsis. In a prospective single-center ICU study, elevated serum creatinine and liver failure on the first day of severe sepsis were associated with subsequent AKI, whereas diabetes was not [13].
In our study, diabetes decreased the likelihood of renal function recovery in patients with se-vere sepsis or septic shock. Clinical practical consequences of this information might be to con-sider involvement of a nephrologist in the early ICU care of patients with diabetes and severe sepsis or septic shock as well as long-term follow-up by a nephrologist after ICU discharge to determine whether these patients eventually recover their previous level of renal function. Dia-betic patients admitted for sepsis severe or septic shock should have explorations including uri-nary sediment and nephrotoxic drugs should be used with caution.
Our study has several limitations however. First, although these patients were extracted from a large multicenter database, we cannot exclude risk of bias related to our matching ap-proach and to differences in patient’s management across sites. Second, diabetic status was as-sessed based on previous medical history as reported by patients, relatives or consultants, so we did not have information on HBA1C levels or exhaustive diabetes complications. Whether hav-ing a poorly controlled diabetes is of worse prognosis or not will be the object of a further Table 3. Odds ratios for acute kidney injury and renal replacement therapy associated with diabetes mellitus in the matched case-control analysis of patients with severe sepsis or septic shock: unadjusted and adjusted conditional logistic regression models.
Matched patients After adjustment
OR [95%CI] Pvalue OR [95%CI] Pvalue
Acute kidney injury
All patients with diabetes 1.18 [1–1,38] 0.05 1.24 [0.79–1.94] 0.34
Insulin-dependent diabetes 1.37 [1.04–1.81] 0.02 2.51 [0.94–6.65] 0.07
Non-insulin-dependent diabetes 1.09 [0.89–1.33] 0.4 1.05 [0.64–1.72] 0.9
Renal replacement therapy
All patients with diabetes 1.09 [0.79–1.49] 0.6 1.03 [0.51–2.08] 0.9
Insulin-dependent diabetes 1.09 [0.62–1.91] 0.8 2.08 [0.42–10.12] 0.4
Non-insulin-dependent diabetes 1.09 [0.74–1.59] 0.7 0.87 [0.40–1.92] 0.7
OR, odds ratio; 95% CI, 95% confidence interval
doi:10.1371/journal.pone.0127411.t003
Table 4. Renal function at ICU discharge in patients with severe sepsis or septic shock who experienced acute kidney injury during the ICU stay and were discharged alive.
All cases and controls Matched cases and controls
Diabetes (N = 244)
No diabetes (N = 1312)
P value
Diabetes (N = 174)
No diabetes (N = 357)
P value
Serum creatinine (μmol/L), median,
[interquartile range]
127 [93–206] 115 [79–184] <0.01 134 [104–239] 103 [75–155] <0.001
Recovery of renal function, n (%) 114 (48.1) 700 (54.4) 0.08 69 (41.1) 214 (60.5) <0.001 Persistent renal dysfunction at ICU
discharge
KDIGO category 3, n (%) 54 (22.8) 225 (17.5) 0.05 43 (25.7) 53 (15) <0.01 Patients still on RRT, n (%) 20 (8.9) 72 (5.6) 0.05 16 (9.5) 17 (4.8) 0.02
RRT, renal replacement therapy
Comparison of all cases (with diabetes) and controls (without diabetes) and comparison of matched cases and controls
study. Third, we excluded patients with CKD. However, some of these patients may have been missed, as detailed information on pre-ICU renal function was not always available. In addi-tion, some cases of prerenal AKI, or rapidly reversible AKI, may have been missed. Fourth, AKI was diagnosed according to the KGDIGO guidelines but only based on serum creatinine variations, as urinary output was not available in the database, which can not be corrected ret-rospectively [24]. Fifth, the use of RRT was not based on standardized criteria but was instead upon clinicians’decision as standardized recommendations do not exist and as strategies differ across sites, like in most previous studies. Finally, no long-term follow-up was available in this database, which is a limitation as previous studies have shown that renal recovery must be eval-uated no earlier than one year after an acute kidney injury episode [25].
No nephrologist consultant was involved in patients’management. However, in all partici-pating ICUs, at least one senior intensivist is a nephrologist. This point can be of interest as previous studies have shown that nephrologist follow-up improves all-cause mortality of severe acute kidney injury survivors [26].
Long-term follow-up including determination of diabetes control and analysis of urinary sediment is warranted.
In summary, in patients with severe sepsis or septic shock, diabetes is not associated with AKI or RRT but is an independent risk factor for failure to recover the previous level of renal function by ICU discharge. Involvement of a nephrologist in the early ICU care of patients with diabetes and severe sepsis or septic shock deserves consideration, as well as a long-term follow-up by a nephrologist after ICU discharge.
Acknowledgments
We are indebted to the persons listed below for their participation in the Outcomerea study group.
Scientific committee
Jean-François Timsit (Hôpital Albert Michallon and INSERM U823, Grenoble, France), Elie Azoulay (Medical ICU, Hôpital Saint Louis, Paris, France), Yves Cohen (ICU, Hôpital Avic-enne, Bobigny, France), Maïté Garrouste-Orgeas (ICU Hôpital Saint-Joseph, Paris, France), Lilia Soufir (ICU, Hôpital Saint-Joseph, Paris, France), Jean-Ralph Zahar (Microbiology De-partment, Hôpital Necker, Paris, France), Christophe Adrie (ICU, Hôpital Delafontaine, Saint Denis, France), and Christophe Clec’h (ICU, Hôpital Avicenne, Bobigny, and INSERM U823, Grenoble, France). Biostatistical and informatics expertise: Jean-Francois Timsit (Hôpital Al-bert Michallon and INSERM U823, Grenoble, France), Sylvie Chevret (Medical Computer Sci-ences and Biostatistics Department, Hôpital Saint-Louis, Paris, France), Corinne Alberti (Medical Computer Sciences and Biostatistics Department, Robert Debré, Paris, France), Adrien Français (INSERM U823, Grenoble, France), Aurélien Vesin INSERM U823, Grenoble, France), Christophe Clec’h (ICU, Hôpital Avicenne, Bobigny, and INSERM U823, Grenoble, France), Frederik Lecorre (Supelec, France), and Didier Nakache (Conservatoire National des Arts et Métiers, Paris, France).
Investigators participating in the Outcomerea database
Jean-Pierre Colin (ICU, Hôpital de Dourdan, Dourdan, France), Mickael Darmon (ICU, CHU Saint Etienne), Anne-Sylvie Dumenil (Hôpital Antoine Béclère, Clamart France), Adrien Descorps-Declere (Hôpital Antoine Béclère, Clamart France), Jean-Philippe Fosse (ICU, Hôpital Avic-enne, Bobigny, France), Samir Jamali (ICU, Hôpital de Dourdan, Dourdan, France), Hatem Khallel (ICU, Cayenne General Hospital), Christian Laplace (ICU, Hôpital Kremlin-Bicêtre, Bicêtre, France), Alexandre Lauttrette (ICU, CHU G Montpied, Clermont-Ferrand), Thierry Lazard (ICU, Hôpital de la Croix Saint-Simon, Paris, France), Eric Le Miere (ICU, Hôpital Louis Mourier, Colombes, France), Laurent Montesino (ICU, Hôpital Bichat, Paris, France), Bruno Mourvillier (ICU, Hôpital Bichat, France), Benoît Misset (ICU, Hôpital Saint-Joseph, Paris, France), Delphine Moreau (ICU, Hôpital Saint-Louis, Paris, France), Etienne Pigné (ICU, Hôpital Louis Mourier, Colombes, France), Bertrand Souweine (ICU, CHU G Montpied, Clermont-Ferrand), Carole Schwebel (CHU A Michallon, Grenoble, France), Gilles Troché (Hôpital Antoine, Béclère, Clamart France), Marie Thuong (ICU, Hôpital Delafontaine, Saint Denis, France), Guillaume Thierry (ICU, Hôpital Saint-Louis, Paris, France), Dany Toledano (CH Gonnesse, France), and Eric Vantalon (SICU, Hôpital Saint-Joseph, Paris, France).
Study monitors
Caroline Tournegros, Loic Ferrand, Nadira Kaddour, Boris Berthe, Samir, Bekkhouche, and Sylvain Anselme
Author Contributions
Conceived and designed the experiments: MV LW CC EA. Performed the experiments: MV LW CC EA. Analyzed the data: MV LW CC EA. Contributed reagents/materials/analysis tools: MV LW CC MD BA DGT MGO CA JFT EA. Wrote the paper: MV LW CC MD BA DGT MGO CA JFT EA.
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